Prostate cancer is the most common cancer among men in the United
States and Canada.[sup.1,2] The 5-year disease-specific survival for men
with all stages of prostate cancer combined is 98.8%.[sup.3] Androgen
deprivation therapy (ADT) using gonadotropin-releasing hormone (GnRH)
agonists is now commonly prescribed for men with locally advanced or
high-risk localized disease in addition to men with metastatic
disease.[sup.4,5] Androgen deprivation therapy has been to shown to
improve survival for men in these disease groups, but long-term androgen
deprivation has also been associated with important side effects in a
variety of areas, including osteoporosis, diabetes, anemia and possibly
cardiovascular disease.[sup.6,7]

Although several large retrospective studies using administrative
data have shown an increased risk of developing diabetes with GnRH
use,[sup.8,9] these studies often lack detailed clinical information
about patients; data from prospective studies have been limited.
Findings by Dockery and colleagues demonstrated that ADT did not affect
blood glucose levels over a 3-month period.[sup.10] Another study
reported an increase in fasting glucose and insulin requirements in
diabetic patients undergoing ADT for a 2-year period.[sup.11] The impact
of longer-term ADT use on blood glucose levels in non-diabetic patients
has not been reported.

Studies demonstrating lipid alterations with ADT have been somewhat
contradictory. Early research showed that ADT caused an increase in
total cholesterol, high-density lipoprotein (HDL), and triglyceride
levels in 50 patients with benign prostatic hyperplasia.[sup.12]
Conversely, a large, recent study showed a decrease in HDL and an
increase in low-density lipoprotein (LDL), triglycerides and total
cholesterol with 12-month use of ADT.[sup.13] Prior studies have
generally featured small sample sizes, and have not consistently
accounted for patient medication use, smoking history, body mass index
(BMI) and previous diseases.[sup.14] Independently, all of these factors
have an effect on blood cholesterol levels, and need to be accounted for
to understand the effects of ADT.

We sought to investigate the effects of ADT on blood glucose and
blood cholesterol over a 12-month period in a prospective matched cohort
study.

Materials and methods

We approached English-speaking patients with non-meta-static
prostate cancer attending Princess Margaret Hospital, a tertiary care
cancer centre in Toronto, Canada, to take part in this pilot study.
Recruited patients were part of a larger, prospective longitudinal
cohort study investigating side effects and quality of life in patients
undergoing ADT. The ADT cohort consisted of men who were initiating
continuous ADT for at least 12 months. A control group, consisting of
men with prostate cancer but not on ADT, was also recruited. Men in the
ADT cohort were frequency matched to controls on age, education and BMI.
Patients with another active malignancy or major neuropsychiatric
abnormalities were excluded. All patients provided written, informed
consent. The study was approved by the institutional Research Ethics
Board.

The study consisted of 2 visits. The baseline visit was done prior
to patients initiating ADT. Sociodemographic information, smoking and
alcohol use, medication use and other comorbidities were collected from
patients and the patient's electronic health record by a trained
research assistant. In addition, the health record was used to collect
specific disease information. Height and weight were measured using
standardized instruments at baseline to compute the BMI. Lastly,
physical fitness was measured using a 6-minute walk test (a submaximal
exercise test in which the distance a patient walks in 6 minutes is
measured).[sup.15]

Each patient was asked to return for a second visit after 12 months.
Patients reported whether they had started taking any new medications,
or had developed any new comorbidities over the course of the year.
Fasting morning blood work was obtained to measure plasma glucose, HDL,
LDL, triglycerides and total cholesterol. Samples were collected and
analyzed immediately in a reference laboratory where possible, or else
in commercial labs following standard procedures.

Statistical analyses

Baseline characteristics were described using means for continuous
variables and counts for categorical variables. To compare the two
cohorts, Student's t-tests and chi-square tests were used for
continuous and categorical variables, respectively. To determine whether
ADT use was associated with either glucose levels or total cholesterol
levels, we performed univariate linear regression. Patients with prior
or current diabetes were excluded from the glucose analysis, and
patients taking cholesterol-lowering medication (including statins,
fibric acid derivatives, binding resins, and ezetimibe) were excluded
from the cholesterol analysis. We then built multivariable linear
regression models for both outcome variables using a hybrid selection
approach to minimize overfitting given the modest sample
size.[sup.16,17] Variables were included in the multivariable model if
they were statistically significant in the univariate analysis with a
less restrictive p value of 0.20.[sup.16] Age and BMI were forced into
the models based on prior studies demonstrating relationships with
insulin resistance and hyperlipidemia. Variables were subsequently
removed if their p value was >0.10 to create a more parsimonious
model. Because of laboratory or administrative error, 8 subjects had 1
or more missing cholesterol fractions measured beyond total cholesterol.
As such, only total cholesterol was examined in regression models. All
statistical analyses were done using SAS version 9.1 (SAS Institute
Inc., Cary, NC).

Results

A total of 75 patients were recruited, 38 of whom initiated ADT. The
mean overall age of the patients was 68.9 years (range 53-87). In
general, the 2 groups were well-matched with respect to age,
sociodemographic variables, BMI and fitness levels (Table 1). As
anticipated, patients in the ADT cohort had higher stage disease with
worse Gleason scores than controls (Table 1). Twelve patients (6 ADT
users, 6 controls) had prior diabetes and were excluded from the glucose
analysis. A total of 29 patients (17 ADT users, 12 controls) reported
taking cholesterol-lowering medication at baseline, and were excluded
from the cholesterol analysis. No patient developed diabetes or started
taking cholesterol-lowering medication between baseline and the 12-month
visit.

Effect of ADT on blood glucose

In unadjusted analyses, ADT users had a significantly higher
12-month fasting glucose level compared to controls (p = 0.024). In
univariate analyses, ADT use was the strongest statistically significant
independent predictor of fasting glucose. Hypertension and smoking were
weakly associated (p < 0.20) with fasting glucose. The remaining
variables were not good predictors of fasting glucose (data not shown).
In multivariable analyses, ADT use remained a statistically significant
predictor of fasting glucose level (p < 0.03) when all of the
variables were included (full model) and in a reduced model with the
least significant predictors (alcohol use, hyperlipidemia and BMI)
removed (Table 3).

Effect of ADT on cholesterol

In unadjusted analyses, ADT users tended to have higher levels of
total cholesterol, HDL, LDL and triglycerides compared to controls,
although none of the differences were statistically significant (Table
2).

In univariate analyses, only age and hypertension were significant
predictors of total cholesterol (p = 0.011 and 0.015, respectively).
These variables remained significant in both the full and reduced
multivariable models. In the latter model, smoking had a trend towards
significance (p = 0.09). All 3 aforementioned variables were negatively
correlated with total cholesterol. Androgen deprivation therapy use was
not a significant predictor in any of the cholesterol models (Table
4).

Discussion

We compared fasting blood glucose and total cholesterol levels in a
group of ADT users and a matched group of controls. We found that 12
months of ADT use was associated with higher fasting glucose levels than
among controls. However, although cholesterol levels tended to be higher
in ADT users, these were not statistically significant. We found no
other predictor of fasting glucose among the variables analyzed, whereas
increasing age and hypertension were associated with slightly lower
total cholesterol levels in adjusted models.

The fasting glucose results demonstrated in our study build on past
studies. Dockery and colleagues demonstrated there was no change in
fasting glucose within 3 months after starting ADT.[sup.10] However,
they had a small sample size (n = 16) and only followed patients for 3
months. A longer follow-up period may have yielded more conclusive
results. Research by Basaria and colleagues demonstrated that the degree
of insulin resistance and hyperglycemia are directly related to the
duration of ADT.[sup.18] Once again, this study had a very small sample
size (n = 18), there was no control group, and patients had been on ADT
for varying periods of time. Our results build on these prior findings
by demonstrating that ADT use for 1 year is associated with an increase
in fasting glucose levels. These findings are likely due to ADT use as
opposed to prostate cancer or other factors, as all of our controls had
prostate cancer and were matched on age and BMI with ADT users. The
finding of increased fasting glucose levels is also supported by large
studies using administrative data to demonstrate an increased risk of
diabetes with ADT use over time.[sup.8,9]

The cholesterol results obtained in our study are less conclusive
due to the small sample size, but add to the published literature. In a
recently published systematic review of this area, 3 studies analyzing
the effect of ADT on lipid fractions were identified.[sup.14] The
average sample sizes of these studies was small (n = 24-40) and the
studies had varying time points of follow-up, ranging from 24 weeks to 1
year. In all 3 studies, total cholesterol and HDL were found to increase
with ADT use. Inconsistencies were reported with LDL and triglyceride
values, with studies reporting either an increase or no change in the
values. Furthermore, a recent large randomized trial found a decrease in
HDL levels and no increase in total cholesterol with ADT use.[sup.13]
Further study with appropriate controls is thus needed to understand the
effect of ADT on different lipid fractions.

What is the clinical relevance of our findings? It is important for
a clinician starting a patient on ADT to obtain fasting blood glucose
and lipid levels prior to initiating treatment. For patients with frank
diabetes, which remains underdiagnosed,[sup.19] they should be managed
by their primary care physician or diabetic specialist according to
standard guidelines.[sup.20] For those with impaired fasting glucose
(IFG), consideration should be given to lifestyle modification and/or
initiation of metformin to prevent progression to diabetes.[sup.21] For
these patients and for those with normal fasting blood glucose, our
results, combined with prior studies, suggest that repeat glucose levels
should be measured to screen for the development of diabetes at least
once yearly while men remain on ADT. Although the difference in blood
glucose between men on ADT and controls may seem small (0.36 mmol/L), it
is likely clinically significant for 2 reasons. First, in the setting of
IFG, glucose levels range from 6.1 to 7.0 mmol/L. Thus, a rise of about
0.4 mmol/L would shift almost half these patients into the category of
diabetes, with obvious prognostic and therapeutic implications. Second,
intensive lifestyle modifications, metformin and rosiglitazone have been
shown to decrease progression to diabetes from IFG by 30% to 60% in
large randomized trials.[sup.21,22] In these trials, the average
decrease in blood glucose level was in the range of 0.3 to 0.5 mmol/L,
similar to our observed difference. These data would suggest the effect
of ADT on developing diabetes is particularly relevant for men who are
already at risk (i.e., men with IFG).

For men with elevated cholesterol levels, management should be
dictated by cardiovascular risk factors. It remains unclear whether we
should monitor or manage these patients differently because of
concomitant ADT use.

Our study did have a number of limitations. The 2 key ones were lack
of blood measurement at baseline and small sample size. Our study began
in 2004, at which time little was known about the impact of ADT on
glucose or lipids. Partway through our study, we added measurements of
fasting glucose and lipids, but could only obtain 12-month measurements
at that point. It is possible that ADT users had elevated blood glucose
levels prior to starting ADT, although other cardiovascular risk
factors, BMI, other comorbidity, age, educational level and physical
fitness were similar among ADT users and controls, making this unlikely.
However, prospectively collected blood measurements over multiple time
points would clearly be helpful. We also recognize that our sample size
is fairly small (75 patients). After excluding diabetic patients (n =
12) and patients on cholesterol medications (n = 29) the sample sizes
for the 2 groups were reduced further. Thus, it is likely that this is
the reason why statistically significant differences were not observed
in the lipid fractions between ADT users and controls.

Furthermore, due to laboratory and administrative errors, some
patients did not have several lipid fractions measured. Despite this,
differences in fasting glucose were statistically significant.
Generalizability may also be an issue, as only English-speaking patients
from a single tertiary care centre were recruited. Thus, further
longitudinal studies with a larger sample and more diverse population of
prostate cancer patients are required to confirm these results. Further
longitudinal analyses examining changes in other lipoprotein components
(e.g., apolipoprotein B100) among ADT users and controls, as well as
following patients for a longer time period to assess changes in lipid
fractions, could also provide valuable information and a greater
understanding of the possible adverse cardiovascular and metabolic
effects of ADT.

Conclusion

We demonstrated that 1 year of ADT use increased serum fasting
glucose; however, the effects on serum total cholesterol, HDL, LDL and
triglyceride levels are less clear in men with non-metastatic prostate
cancer.

Acknowledgements

Mr. Mohamedali was supported by the Oskar Ascher Schmidt Fund. The
study was funded by the Canadian Cancer Society. Dr. Alibhai is a
Research Scientist of the Canadian Cancer Society.

19. Narayan KM, Thompson TJ, Boyle JP, et al. The use of population
attributable risk to estimate the impact of prevention and early
detection of type 2 diabetes on population-wide mortality risk in US
males. Health Care Manag Sci 1999;2:223-7.